ABSRACT: Emphysema and chronic bronchitis comprise the syndrome of COPD, now surpassing stroke as the 3rd leading cause of death in the US and a highly prevalent disease in Veterans. Alpha 1 antitrypsin (A1AT) is an abundant protein released by the liver, with outreaching systemic actions. The discovery of the A1AT inhibitory function against neutrophil elastase implicated the lung matrix proteolysis as a major pathogenic mechanism of emphysema and prompted the study of A1AT as therapy for emphysema patients. While proven effective for select patients with A1AT-deficiency, A1AT replacement has disappointed as treatment for cigarette smoke (CS)-induced emphysema. We propose to improve the therapeutic potential of A1AT for emphysema by optimizing its vascular protective effects. Our proposal pursues the novel hypothesis that A1AT has a vascular protective function in addition to its canonical anti- elastase serpin function, by opposing cytokine-induced endothelial activation, but that inflammatory cytokines and CS degrade and decrease the abundance of A1AT in endothelial cells. Since endothelial vascular cells are the first defense against inflammation, optimizing the retention and function of A1AT within the endothelium might decrease inflammation, and may halt emphysema progression. This application dissects the factors and mechanisms that affect the retention of A1AT in lung endothelial cells (Aim 1), and studies approaches to optimize the vascular protective effects of A1AT (Aim 2). We rely on an integrated approach involving the CS model of emphysema characterized by lung inflammation and endotehlial cell apoptosis, on live cell and animal imaging of A1AT intracellular fate in the lung microcirculation, and on molecular and pharamcoligical approaches to increase the A1AT vascular retention during short- and long- term CS exposure. Our proposal, while focusing on COPD, has broader impact with regards to serpin biology and the pathobiology of systemic and pulmonary vascular diseases characterized by inflammation.